Radiosensitivity in patients affected by ARPC1B deficiency: a new disease trait?

Abstract

Actin-related protein 2/3 complex subunit 1B (ARPC1B) deficiency is a recently described inborn error of immunity (IEI) presenting with combined immunodeficiency and characterized by recurrent infections and thrombocytopenia. Manifestations of immune dysregulation, including colitis, vasculitis, and severe dermatitis, associated with eosinophilia, hyper-IgA, and hyper-IgE are also described in ARPC1B-deficient patients. To date, hematopoietic stem cell transplantation seems to be the only curative option for patients. ARPC1B is part of the actin-related protein 2/3 complex (Arp2/3) and cooperates with the Wiskott–Aldrich syndrome protein (WASp) in the regulation of the actin cytoskeleton remodeling and in driving double-strand break clustering for homology-directed repair. In this study, we aimed to investigate radiosensitivity (RS) in ARPC1B-deficient patients to assess whether it can be considered an additional disease trait. First, we performed trio-based next-generation-sequencing studies to obtain the ARPC1B molecular diagnosis in our index case characterized by increased RS, and then we confirmed, using three different methods, an increment of radiosensitivity in all enrolled ARPC1B-deficient patients. In particular, higher levels of chromatid-type aberrations and γH2AX foci, with an increased number of cells arrested in the G2/M-phase of the cell cycle, were found in patients’ cells after ionizing radiation exposition and radiomimetic bleomycin treatment. Overall, our data suggest increased radiosensitivity as an additional trait in ARPC1B deficiency and support the necessity to investigate this feature in ARPC1B patients as well as in other IEI with cytoskeleton defects to address specific clinical follow-up and optimize therapeutic interventions.

Targeted treatments for immune dysregulation in inborn errors of immunity

“…Majeed syndrome [48] IEIs with significant cutaneous atopy Wiskott Aldrich syndrome [61] ARPC1B deficiency DOCK8 deficiency [62][63][64][65][66][67][68][69][70] CARD11 deficiency [62][63][64][65][66][67][68][69][70] Netherton syndrome [62][63][64][65][66][67][68][69][70] RAG1/RAG2 immunodeficiency [62][63][64][65][66][67][68][69][70] STAT3 LOF [62][63][64][65][66][67][68][69][70] ZNF341 deficiency [62][63][64]...…”

Tailored treatments in inborn errors of immunity associated with atopy (IEIs-A) with skin involvement

“…ARPC1B protein is a component of the actin-related protein 2/3 complex (Arp2/3) and together with WASp regulate cytoskeletal remodeling of actin and the DNA damage response ( 21 ).…”

“…We recently reported a substantial improvement of eczema after starting dupilumab in an ARPC1B child whose phenotype was characterized by frequent infections, thrombocytopenia, elevated eosinophils, IgA and IgE levels, vasculitis, colitis and severe dermatitis refractory to conventional medical therapy. At the age of 10 years, she received dupilumab with significant improvement of dermatitis and itchiness ( 21 ).…”

Autoimmune and autoinflammatory manifestations in inborn errors of immunity

“…Increased radiosensitivity was also shown in ARPC1B-deficient patients with higher levels of chromatid-type aberrations and γH2AX foci as a measure of DNA damage. This feature can be attributed to decreased driving of double-strand break clustering for homology-directed repair because of decrease in actin cytoskeleton remodelling [52 ▪ ]. Increased radiosensitivity can have an important effect on optimizing therapeutic interventions and specific follow-up since hematopoietic stem cell transplantation seems to be the only curative option for this group of patients [53].…”